Current evidence indicates that morphine and related opiates possess the ability to alter the storage, release, synthesis and/or receptor actions of endogenous neurotransmitters, hormones and modulator autocoids in the intestine. These actions of the opiates account for many of their complicated intestinal motor actions and result in failure of propulsion. Experiments to date demonstrate that the intestinal spasm induced by narcotic drugs is accompanied by release of 5-hydroxytryptamine (5-HT) from local storage sites. 5-HT may play a central role in the development of the spasmogenic effect of the opiates. Morphine-induced intestinal contractions may be accompanied also by release of prostaglandins. The purposes of this investigation are (1) to explore further the role of 5-HT as a mediator of opiate effects on the intestine, (2) to identify those motor components of morphine action which cause constipation, (3) to examine the mechanisms of prostaglandin modulation of opiate contractions, (4) to determine whether intestinal hormones participate in responses to opiates, (5) to measure cyclic nucleotide levels in response to adrenergic amines, prostaglandins and inhibitors of phosphodiesterase, and (6) to establish optimal pharmacological means for selective enhancement or inhibition of intestinal responses to opiates. These studies will be conducted in dog isolated intestinal segments, in dog intestine in situ and on rat intestinal propulsion in vivo. These studies will help define the mechanisms of opiate actions on the intestine, will reveal the roles of endogenous substances as mediators and modulators of physiological activities, and will provide the pharmacological basis for more rational therapeutic use of the potent analgesic drugs.